Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib

Broxterman, Henk J.; Gotink, Kristy J.; Verheul, Henk M.W.

doi:10.1016/j.drup.2009.07.001

Cited by 190 publications

(138 citation statements)

References 205 publications

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“…Two major downstream signaling pathways stimulated by RTKs include the Ras/Raf/MEK/ERK and PI3K/AKT pathways that play a central role in proliferation and survival of cancer cells. It has also been reported previously that resistance to some anticancer drugs in cancer cells can be decreased by inhibiting the AKT and ERK1/2 pathways (23,24). To investigate the effect of sorafenib on ABCG2 via the suppression of the AKT and ERK1/2 protein activity, we examined the change of total and phosphorylated forms of AKT and ERK1/2 after treatment with sorafenib at ABCG2 reversal concentration in both the resistant and parental cells.…”

Section: Dual Action Of Sorafenib On Abcg2mentioning

confidence: 99%

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Wei

Zhao

et al. 2012

Molecular Cancer Therapeutics

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Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizing MDR in cancer chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with novel chemical structures. One efficient solution is to rediscover new uses for existing drugs with known pharmacokinetics and safety profiles. Here, we found the new use for sorafenib, which has a dual-mode action by inducing ABCG2 degradation in lysosome in addition to inhibiting its function. Previously, we reported some novel dual-acting ABCG2 inhibitors that showed closer similarity to degradation-induced mechanism of action. On the basis of these ABCG2 inhibitors with diverse chemical structures, we developed a pharmacophore model for identifying the critical pharmacophore features necessary for dual-acting ABCG2 inhibitors. Sorafenib forms impressive alignment with the pharmacophore hypothesis, supporting the argument that sorafenib is a potential ABCG2 inhibitor. This is the first article that sorafenib may be a good candidate for chemosensitizing agent targeting ABCG2-mediated MDR. This study may facilitate the rediscovery of new functions of structurally diverse old drugs and provide a more effective and safe way of sensitizing MDR in cancer chemotherapy.

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Section: Dual Action Of Sorafenib On Abcg2mentioning

confidence: 99%

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Wei

Zhao

et al. 2012

Molecular Cancer Therapeutics

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“…Several mechanisms have been suggested to participate in conferring platinum-resistant properties to a tumour cell such as genetic alterations in genes involved in DNA repair, drug uptake, apoptosis, cell cycle control and IGF signalling pathways (Johnstone et al, 2002;Luqmani, 2005;Edwards et al, 2008;Broxterman et al, 2009;Eckstein et al, 2009). More recently, it has been proposed that, in addition to genetic changes, aberrant epigenetic marks can critically contribute to the acquisition of drug resistance (Sharma et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

et al. 2012

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Multiple DNA methylation changes in the cancer methylome are associated with the acquisition of drug resistance; however it remains uncertain how many represent critical DNA methylation drivers of chemoresistance. Using isogenic, cisplatin-sensitive/resistant ovarian cancer cell lines and inducing resensitizaton with demethylating agents, we aimed to identify consistent methylation and expression changes associated with chemoresistance. Using genome-wide DNA methylation profiling across 27 578 CpG sites, we identified loci at 4092 genes becoming hypermethylated in chemoresistant A2780/cp70 compared with the parental-sensitive A2780 cell line. Hypermethylation at gene promoter regions is often associated with transcriptional silencing; however, expression of only 245 of these hypermethylated genes becomes downregulated in A2780/cp70 as measured by microarray expression profiling. Treatment of A2780/ cp70 with the demethylating agent 2-deoxy-5 0 -azacytidine induces resensitization to cisplatin and re-expression of 41 of the downregulated genes. A total of 13/41 genes were consistently hypermethylated in further independent cisplatin-resistant A2780 cell derivatives. CpG sites at 9 of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS and PSMB9) acquired methylation in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 genes (ARMCX2, COL1A1, MDK, MEST and MLH1) acquired methylation in drug-resistant ovarian cancersustaining (side population) cells. MLH1 has a direct role in conferring cisplatin sensitivity when reintroduced into cells in vitro. This combined genomics approach has identified further potential key drivers of chemoresistance whose expression is silenced by DNA methylation that should be further evaluated as clinical biomarkers of drug resistance.

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“…Previous studies have demonstrated that DOX can induce apoptosis in leukemic cells in vivo and in vitro (11). However, de novo and acquired resistances to DOX are also widely observed, the mechanism of which appears to be complex and heterogeneous (12). Better understanding of the mechanism of DOX resistance should aid to treat patients with leukemia more effectively.…”

Section: Introductionmentioning

confidence: 99%

Ikaros expression sensitizes leukemic cells to the chemotherapeutic drug doxorubicin

Gao

Zhu

et al. 2016

Oncology Letters

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Abstract.Ikaros is an important transcription factor involved in the development and differentiation of hematopoietic cells. However, its role in the treatment of hematopoietic malignancies such as leukemia is less well understood. In the present study, it was observed by data mining of the Oncomine database that high expression levels of full-length Ikaros (IK1) is correlated with increased sensitivity of cancer cells to treatments with chemotherapeutic drugs, including doxorubicin (DOX). To examine the functional significance of this observation, the expression of IK1 in a leukemia cell line was altered, and the response of leukemic cells to DOX treatment was analyzed. It was observed that overexpression of IK1 could enhance DOX-induced apoptosis, while knockdown of IK1 attenuated DOX-induced apoptosis in leukemic cells. Further experiments demonstrated that IK1 sensitized leukemic cells to DOX-induced apoptosis, probably through upregulation of caspase-9. These data suggest that high expression levels of IK1 may be a potential biomarker to predict responses of leukemia patients to treatment with chemotherapy.

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Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib

Cited by 190 publications

References 205 publications

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

Ikaros expression sensitizes leukemic cells to the chemotherapeutic drug doxorubicin

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